1. Field of the Invention
The present invention relates to a method for assessment of tumors, especially relates to a novel method of non-invasive measurement of tumor hemodynamic parameters to detect the degree of malignancy in tumors.
2. The Prior Arts
Tumor blood flow plays an important role for tumor growth and metastasis from the view of tumor metabolism. It's also crucial to the selection of optimal therapy and a marker for response to therapy. Jain reviewed the current knowledge of physical parameters for normal, benign and malignant neoplastic tissues in Cancer Research, volume 48(10): 2641-58, 1988. Non-invasive techniques for assessment of tumors like magnetic resonance imaging (MRI), ultrasound B-Mode Image are known for imaging tumor sizes, structures of blood vessels in tumors, vascular network of tumor, integrity of tumor surface, resistance indices such as pulsed index (PI) and resistance index (RI), and so on. The outcomes of aforementioned detection are limited to suitability when compared with the results of invasive tumor sampling with blood vessel staining or with those of cell culture. This is due to many insufficient assumptions on detection of images and lack of precise quantification indexes, which results not enough credibility.
The degree of angiogenesis in tumors is closely related to the malignancy of tumors, even to the survival rate of therapy. During angiogenesis, microvascular endothelial cells proliferate rapidly which cause only single layer of endothelial cells in the neovascular wall. Consequently, the blood flow of neovasculature is significantly different from that of normal blood vessel under the action of pulsatile blood pressure. Therefore, detection of macroscopic or microscopic blood flow on the artery vessel wall for tumor growth and its hemodynamics are of important values.
Owing to the broad clinical applications of color Doppler ultrasound, one of the inventors of the present invention, Dr. Hsieh, Fon-Jou, published a paper: “Incremental angiogenesis assessed by color Doppler ultrasound in the tumorigenesis of ovarian neoplasms” in Cancer (1994, volume 73(4):1251-6). The crucial role of angiogenesis in malignancy of ovarian neoplasms was confirmed with hemodynamic parameters of PI and RI by color Doppler ultrasound analysis. The following publications related to the clinical applications of color Doppler ultrasound analysis also proved the significance of hemodynamics between the development of cervical cancer and the effects of chemotherapy. U.S. Pat. No. 6,112,108 disclosed a method using Doppler technique to evaluate the nature of diastolic flow within tumors (the time-decay constant of a post-systolic tumor blood-flow waveform) as a means of inferring the vascular resistance, and thus the likelihood of malignancy.
People skilled in the art understand that arterial vessels in tumors are either difficult to locate or many vessels are found all at once. And the differences among vessels are quite significant which result in problems for carrying out the abovementioned method. There is therefore a need for an easy-to-diagnose method with more physical meanings for reliably and accurately assessing the likelihood of malignancy of tumors. Hsieh et al. first used vascularity index (VI) as a novel parameter for the in vivo assessment of angiogenesis in tumors with power Doppler imaging technique (“Usefulness of Doppler spectral analysis and power Doppler sonography in the differentiation of cervical lymphadenopathies.” AJR Am J Roentgenol. 1998, Vol. 171(2):503-9). The concepts of PI and RI indices were extended to vascularity index (VI). VI is of great clinical value in classification of the stages in cervical carcinoma. The color Doppler vascularity index (CDVI) can represent the known quantitative vascular signals of color Doppler sonography. The CDVI is defined as the ratio of the number of the colored pixels (area for blood vessels on which blood stream can be detected by color Doppler ultrasound units) within a tumor section (Region of Interest, ROI) to the number of total pixels (area for tumor) in that specific tumor section during systolic stage. In other words, the CDVI reflects the ratio of running blood vessels inside the tumor. The value of CDVI is higher in the patients with malignant tumors or metastatic cancers. The CDVI can be defined by the following formula:CDVI=the measure of color area in ROI/the measure of ROI areaAnd Power Doppler ultrasound (US) is superior to conventional color Doppler imaging in the detection of blood flow because of its high sensitivity to low flow rates in small vessels.
In addition, U.S. Pat. No. 5,860,929 described a method for quantitatively estimating the amount of tissue that contains moving blood in tissue for a region of interest using power Doppler ultrasound. The power Doppler image of the soft tissue blood volume is scanned in fixed time interval from a frozen image (Frozen ROI). When a pixel value with a power level is greater than the particular intensity threshold, the Doppler power level of said pixel will be summed to the total power level. The fractional moving blood volume (FMBV) is calculated by dividing the total power by the number of Reference Doppler Power Level and total pixels in the region of interest pixels (the measure of ROI area).
Even though the abovementioned methods provide a preliminary quantitative tool for tumor classification, tumors containing soft tissue and blood vessels are highly versatile which makes the representative frozen image difficult to take. In addition, no standardized threshold causes the range of CDVI parameter being limited to the function of scanner hardware or affected by the scanning parameters. People have suggested an addition of ultrasonic Contrast Agent to raise the resolution of blood stream in power Doppler. U.S. Pat. No. 6,315,730 even revealed an effective amount of an ultrasound contrast agent which is designed to be particularly sensitive to disruption by the initial ultrasound pulse(s), thereby limiting the intensity required for the initial ultrasound irradiation to obtain a more accurate vascularity ratio. However, the improvement is still limited. Moreover, prior arts did not consider the interaction timing mechanism within tumor vascularity biomedical physics, which caused the goals of scientific and automatic diagnosis difficult to reach.
Although traditional vascularity index (VI) can be used to classify the tumor stage, the assessment of angiogenesis in tumors is preferred to be a better parameter for tumor development, malignancy and metastasis. Since the blood supply in tumor varies with the contents of arterial vessels and venous vessels in vivo, using only total VI of tumor to classify the tumor stage is not accurate enough physiologically.
In addition, the CDVI parameter determined by the known techniques is easily affected by scanning range (ROI). When the borderline of tumor is not significant clear, the measure errors due to sampling of section will affect seriously in the value of CDVI. And the known method used to choose the single image is fixed in the maximal systole. The image chosen may not be representative, and the total blood vessel areas measured are not necessarily right. Because the blood stream is continuously flowing, the area of Doppler images during the whole heartbeat cycle should be considered.